LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-31
Case ID: NM_002168.4_c.515G_A_20261031_091537
Framework: ACMG/AMP 2015
Variant classification summary

NM_002168.4:c.515G>A

IDH2  · NP_002159.2:p.(Arg172Lys)  · NM_002168.4
GRCh37: chr15:90631838 C>T  ·  GRCh38: chr15:90088606 C>T
Gene: IDH2 Transcript: NM_002168.4
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
IDH2
Transcript
NM_002168.4
Protein
NP_002159.2:p.(Arg172Lys)
gnomAD AF
6.19484266958072e-07 (v4.1)
ClinVar
risk factor
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong—IDH2 R172K showed approximately 100-fold increased intracellular 2HG and concordant disease-relevant functional effects.
2
Likely Pathogenic: PM1 moderate—Arg172 is a recurrent IDH2 mutational hotspot, and the exact variant is reported 467 times in COSMIC.
3
Likely Pathogenic: PM2 supporting—gnomAD v4.1 allele frequency is 6.19e-07 with zero homozygotes.
4
Likely Pathogenic: PP3 supporting—REVEL 0.733 meets the adjudicated threshold of at least 0.644.
Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong pathogenic criterion plus 1 Moderate and 1-2 Supporting pathogenic criteria supports Likely Pathogenic; no benign rule is satisfied.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: R172K is reported in cancer studies, but no previously established pathogenic classification is documented for this exact amino-acid change.
clinvar PMID:20171147 PMID:25043045
PS2 Not assessed Not assessed: no documented de novo observation with confirmed maternity and paternity or an established absence of family history.
PS3 Met Met: IDH2-R172K produced approximately 100-fold more intracellular 2HG than vector or wild-type controls and showed concordant biochemical, cellular, and mouse-model effects.
PMID:20171147 PMID:25043045
PS4 Not assessed Not assessed: no affected-case versus control counts or case frequency were available to calculate the required OR >5.0 and 95% CI excluding 1.0.
PMID:20171147 PMID:34131312 gnomad_v4
PM1 Met Met: IDH2 Arg172 is a recurrent hotspot, with the exact variant reported 467 times in COSMIC and identified in a statistically significant hotspot.
hotspots cosmic PMID:21326614
PM2 Met Met at supporting: gnomAD v4.1 total AF is 6.19e-07 (1/1,614,246 alleles), below the <=0.0001 PM2 threshold, with zero homozygotes.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: no recessive inheritance, pathogenic second allele, or parental/offspring phase testing is documented for this heterozygous somatic variant.
clinvar PMID:20171147
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not met Not met: R172M and R172G are reported at the same residue, but neither is established as pathogenic under generic ACMG/AMP evidence.
pm5_candidates PMID:21326614
PM6 Not assessed Not assessed: no documented assumed-de novo observation or parental testing establishes de novo status without confirmed maternity and paternity.
PP1 Not assessed Not assessed: no affected family members, informative meioses, or variant segregation results are documented for co-segregation analysis.
PP2 Not assessed Not assessed: the case lacks gene-wide benign-missense and germline disease-mechanism data required to establish both PP2 components.
gnomad_v4 PMID:20171147 PMID:21326614
PP3 Met Met at supporting strength: REVEL 0.733 meets the generic PP3 threshold of >=0.644 for this missense variant.
revel
PP4 Not assessed Not assessed: no patient phenotype or family-history information was available to judge specificity for a disease with a single genetic etiology.
PP5 Not met Not met: ClinVar shows no exact-variant expert-panel Pathogenic or Likely pathogenic classification, and the proposed paper does not mention IDH2 c.515G>A.
clinvar PMID:34131312
BA1 Not met Not met: gnomAD v4.1 total AF is 6.19e-07, far below the >=0.05 BA1 threshold, with no qualifying grpmax FAF above threshold.
gnomad_v4 gnomad_v2
BS1 Not met Not met: gnomAD v4.1 total AF is 6.19e-07, far below the generic >=0.01 BS1 default, with no qualifying elevated grpmax FAF.
gnomad_v4 gnomad_v2
BS2 Not assessed Not assessed: gnomAD reports zero homozygotes but does not document an unaffected healthy adult carrier or establish the required penetrance and age model.
gnomad_v4 gnomad_v2
BS3 Not met Not met: variant-specific studies showed approximately 100-fold increased intracellular 2HG and impaired differentiation rather than preserved protein function or splicing.
PMID:20171147 PMID:25043045
BS4 Not assessed Not assessed: no affected relatives lacking the variant are documented, so lack of segregation and the phenocopy caveat cannot be evaluated.
BP1 Not met Not met: the available IDH2 evidence emphasizes recurrent Arg172 missense gain-of-function mutations, not a disease mechanism primarily caused by truncating variants.
PMID:20171147 PMID:21326614
BP2 Not assessed Not assessed: no qualifying cis or trans pathogenic-variant observation is documented for this somatic IDH2 R172K variant.
clinvar PMID:20171147
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.733 is above the generic BP4 supporting threshold of <=0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: no case was documented with this variant and an alternate molecular basis for the relevant disease.
BP6 Not met Not met: ClinVar contains no exact-variant expert-panel Benign or Likely benign classification for IDH2 c.515G>A.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.